Modeling fructose-load-induced hepatic de-novo lipogenesis by model simplification

Abstract

Hepatic de-novo lipogenesis is a metabolic process implemented in the pathogenesis of type 2 diabetes. Clinically, the rate of this process can be ascertained by use of labeled acetate and stimulation by fructose administration. A systems pharmacology model of this process is desirable because it facilitates the description, analysis, and prediction of this experiment. Due to the multiple enzymes involved in de-novo lipogenesis, and the limited data, it is desirable to use single functional expressions to encapsulate the flux between multiple enzymes. To accomplish this we developed a novel simplification technique which uses the available information about the properties of the individual enzymes to bound the parameters of a single governing ‘transfer function’. This method should be applicable to any model with linear chains of enzymes that are well stimulated. We validated this approach with computational simulations and analytical justification in a limiting case. Using this technique we generated a simple model of hepatic de-novo lipogenesis in these experimental conditions that matched prior data. This model can be used to assess pharmacological intervention at specific points on this pathway. We have demonstrated this with prospective simulation of acetyl-CoA carboxylase inhibition. This simplification technique suggests how the constituent properties of an enzymatic chain of reactions gives rise to the sensitivity (to substrate) of the pathway as a whole.

Nonalcoholic Fatty Liver Disease: A Challenge from Mechanisms to Therapy

“…Authors found that Pb2+ exposure could be a lethal disruptor of lipid metabolism in hepatocytes, and highlighted sorcin (a cytosolic adaptor partner of carbohydrate responsive element binding protein (ChREBP)-dependent hepatic lipogenesis) as a novel therapeutic target against Pb2+-induced hepatic dyslipidemia [90]. Hepatic de-novo lipogenesis (DNL) is a metabolic process proposed in the pathogenesis of T2DM, with multiple enzymes involved in this process [91].…”

Computational Modeling of Fructose Metabolism and Development in NAFLD

“…Relevant in silico simulations have been reported, including glucose absorption and transportation, hormonal regulation, zonation effects, and the relationship between glucose intake and high-intensity exercise, lipid metabolism in addition to metabolic diseases (Chalhoub et al, 2007a , b ; Hetherington et al, 2012 ; König et al, 2012 ; Sumner et al, 2012 ; Ashworth et al, 2016 ; Naftalin, 2016 ; Noorman et al, 2019 ). Irrespective of the fact that abundant studies have highlighted the important role fructose metabolism plays in metabolic diseases, only a few models have placed emphasis on the fructose metabolism and none of these have reflected the potentially dynamic changes (Allen and Musante, 2017 , 2018 ; Maldonado et al, 2018 ).…”